title: Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: a meta-analysis.
abstract: BACKGROUND
  In investigations of the effectiveness of surgery and adjuvant chemotherapy for gastric cancers, overall survival (OS) is considered the gold standard endpoint. However, the disadvantage of using OS as the endpoint is that it requires an extended follow-up period. We sought to investigate whether disease-free survival (DFS) is a valid surrogate for OS in trials of adjuvant chemotherapy for gastric cancer.
  
  
  METHODS
  The GASTRIC group initiated a meta-analysis of individual patient data collected in randomized clinical trials comparing adjuvant chemotherapy vs surgery alone for patients with curatively resected gastric cancer. Surrogacy of DFS was assessed through the correlation between the endpoints as well as through the correlation between the treatment effects on the endpoints. External validation of the prediction based on DFS was also evaluated.
  
  
  RESULTS
  Individual patient data from 14 randomized clinical trials that included a total of 3288 patients were analyzed. The rank correlation coefficient between DFS and OS was 0.974 (95% confidence interval [CI] = 0.971 to 0.976). The coefficient of determination between the treatment effects on DFS and on OS was as high as 0.964 (95% CI = 0.926 to 1.000), and the surrogate threshold effect based on adjusted regression analysis was 0.92. In external validation, the six hazard ratios for OS predicted according to DFS were in very good agreement with those actually observed for OS.
  
  
  CONCLUSIONS
  DFS is an acceptable surrogate for OS in trials of cytotoxic agents for gastric cancer in the adjuvant setting.
authors.affiliation: Affiliations of authors: Translational Research and Clinical Trial Center, Hokkaido University Hospital, Sapporo, Japan (KO); Biostatistics dpt, INSEM U900, Institut Curie, Paris, France (XP); Mayo Clinic, Rochester, MN (SA, DS); Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea (Y-JB); SWOG Statistical Center, Seattle, WA (JB); Brussels, Belgium (HB); Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Department of Biostatistics, Harvard School of Public Health, Boston, MA (PC); University Clinic Leipzig, University Cancer Center, Leipzig, Germany (FL); Biostatistics and Epidemiology department, Institut Gustave-Roussy, Universite Paris XI, Villejuif, France (SMi, J-PP); Department of Biostatistics, Yokohama City University, Yokohama, Japan (SMo); Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan (YO); Gastro-enterology department, University Hospital Europeen Georges Pompidou, Paris, France (PR); Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan (MS); Tokai Central Hospital, Kakumuhara, Japan (JS); Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan (KS); Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium (EVC); International Drug Development Institute, Louvain-la-Neuve, Belgium (MB, TB); I-BioStat, Hasselt University, Diepenbeek, Belgium (MB, TB).
authors.forename: Koji
authors.initials: K
authors.lastname: Oba
authors.forename: Xavier
authors.initials: X
authors.lastname: Paoletti
authors.forename: Steven
authors.initials: S
authors.lastname: Alberts
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Benedetti
authors.forename: Harry
authors.initials: H
authors.lastname: Bleiberg
authors.forename: Paul
authors.initials: P
authors.lastname: Catalano
authors.forename: Florian
authors.initials: F
authors.lastname: Lordick
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohashi
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pignon
authors.forename: Philippe
authors.initials: P
authors.lastname: Rougier
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sasako
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakamoto
authors.forename: Daniel
authors.initials: D
authors.lastname: Sargent
authors.forename: Kohei
authors.initials: K
authors.lastname: Shitara
authors.forename: Eric Van
authors.initials: EV
authors.lastname: Cutsem
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Tomasz
authors.initials: T
authors.lastname: Burzykowski
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D003362:Cost-Benefit Analysis; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005743:Gastrectomy; D006801:Humans; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic / Q000191:economics; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000601:surgery / Q000628:therapy*; D013997:Time Factors; D016896:Treatment Outcome